Project Summary/Abstract: More than eleven million (45.7%) U.S. Veterans are at least 65 years of age with up to 20% suffering from depression. Late-life depression is a common disorder which is often under-diagnosed and under-treated and has been associated with increased functional impairment regardless of symptom severity. Real-world effectiveness of antidepressants is sub-optimal or incomplete in up to two-thirds of patients with treatment resistant depression (Trivedi, 2006; Rush, 2006). Furthermore, common approaches for treatment resistant depression, such as electroconvulsive therapy and monoamine oxidase inhibitors, are not well accepted by elderly patients or risk significant side effects. Most alarmig, however, is the association between untreated depression and risk of suicide among the Veteran population with 69% of Veteran suicides are among those age 50 years and older. Faced with an aging demographic profile towards a higher proportion of elderly Veterans, evidence-based, effective, safe, and efficient interventions for Veterans with late-life treatment resistant depression (LL-TRD) are critically needed. In collaboration with investigators at the Mount Sinai School of Medicine (MSSM), the study team recently completed a NIMH-sponsored randomized trial in patients with treatment resistant depression, comparing the immediate antidepressant properties of a single infusion of ketamine (KET), an open-channel nonselective N-methyl-D-aspartate (NMDA) receptor antagonist; to midazolam (MID), a benzodiazepine anesthetic. The results of this trial definitively affirmed the rapid antidepressant efficacy of KE. A data sub- analysis showed that older participant's response and remission rates were comparable to those of the younger cohort. However, the study was not powered to answer questions unique to the elderly population of a fixed KET dose. These findings provide the rationale for the current proposal of a single-site, randomized, triple- blind (patient, rater, and anesthesiologist) study. This novel strategy has not been adequately tested. Seventy two Veterans age 55 or older will be randomized to receive a single infusion of KET (0.10 mg/kg, 0.25 mg/kg, or 0.5 mg/kg) or MID (0.03mg/Kg), following an adaptive randomization design. The primary aim is to identify and evaluate the durability of benefit of the best performing of the thre sub- anesthetic doses KET and midazolam Veterans with LL-TRD over a 4-week period. Innovative exploratory aims measure the effects of KET infusion on neurocognition, peripheral biomarkers of cellular plasticity and inflammation, and Pharmaco-electroencephalography. As the first randomized controlled trial of ketamine infusion therapy for elderly Veterans with LL-TRD, this proposal has the potential for a transformative impact on clinical practice. Irrespective of outcome, this project will generate valuable data supporting discovery research on NMDA receptor modulators for serious mood disorders.